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Targeting X-linked inhibitor of apoptosis protein inhibits pancreatic cancer cell growth through p-Akt depletion.

AbstractAIM:
To determine whether lentivirus-mediated shRNA targeting the X-linked inhibitor of apoptosis protein (XIAP) gene could be exploited in the treatment of pancreatic cancer.
METHODS:
Human pancreatic cancer cells Panc-1, Mia-paca2, Bxpc-3 and SW1990, infected with lentivirus, were analyzed by real-time polymerase chain reaction (PCR). Western blotting was used to examine XIAP protein levels, survivin and p-Akt to confirm the result of real-time PCR and determine the possible mechanism. The 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to measure IC₅₀ to determine chemosensitivity to the chemotherapeutic drugs 5-fluorouracil (5-FU) and gemcitabine. A colony assay, MTT assay and a tumorigenicity experiment were used to study cell proliferation in vitro and in vivo. Caspase-3/7 activity, 4',6-diamidino-2-phenylindole-staining and flow cytometric measurements were used to study apoptosis in SW1990 cells.
RESULTS:
XIAP proteins were found to be differentially expressed among pancreatic cancer cell lines Panc-1, Mia-paca2, Bxpc-3 and SW1990. Data of real-time PCR and Western blotting showed that XIAP was reduced persistently and markedly by lentivirus-mediated shRNA. Downregulation of XIAP by transfection with XIAP shRNA resulted in decreased p-Akt expression. XIAP shRNA also inhibited the growth of pancreatic cancer cells in vitro and in vivo, enhanced drug-induced apoptosis and increased chemosensitivity to 5-FU and gemcitabine. Results also suggest that inhibition of XIAP and subsequent p-Akt depletion may have an anti-tumor effect through attenuating the ability of cancer cells to survive.
CONCLUSION:
Lentivirus-mediated gene therapy is an attractive strategy in the treatment of pancreatic cancer and justifies the use of lentivirus in pancreatic cancer gene therapy studies.
AuthorsChun Jiang, Xiao-Ping Yi, Hong Shen, Yi-Xiong Li
JournalWorld journal of gastroenterology (World J Gastroenterol) Vol. 18 Issue 23 Pg. 2956-65 (Jun 21 2012) ISSN: 2219-2840 [Electronic] United States
PMID22736919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites, Antineoplastic
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • RNA, Small Interfering
  • Survivin
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Deoxycytidine
  • Proto-Oncogene Proteins c-akt
  • Caspase 3
  • Caspase 7
  • Fluorouracil
  • Gemcitabine
Topics
  • Antimetabolites, Antineoplastic (pharmacology)
  • Apoptosis (drug effects)
  • Caspase 3 (metabolism)
  • Caspase 7 (metabolism)
  • Cell Line, Tumor
  • Cell Proliferation
  • Deoxycytidine (analogs & derivatives, pharmacology)
  • Down-Regulation
  • Drug Resistance, Neoplasm (genetics)
  • Fluorouracil (pharmacology)
  • Genetic Therapy
  • Humans
  • Inhibitor of Apoptosis Proteins (drug effects, metabolism)
  • Pancreatic Neoplasms (genetics, metabolism, therapy)
  • Proto-Oncogene Proteins c-akt (drug effects, metabolism)
  • RNA, Small Interfering (therapeutic use)
  • Survivin
  • X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)
  • Gemcitabine

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